Epigenetically-mediated gene dysregulation is a common feature associated with human pituitary tumorigenesis. The mechanisms leading to these changes, however, remain largely unknown. In this review, we examine changes responsible for DNA and histone modifications as independent, butpotentially interrlated modes of communication effecting chromatin remodeling. The dynamic properties of the enzymes involved in these reactions is highlighted. We use the fibroblast growth factor receptor 2 (FGFR2) as a model through which the p53-regulating melanoma-associated antigen (MAGE) system is governing in pituitary cells. The pathogenetic and potential therapeutic implications are discussed.

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Hypercalcemia during pregnancy or after delivery is uncommon, and mostly associated with primary hyperparathyroidism (PHPT). If unrecognized, it may increase maternal and fetal morbidity. In a very few patients with PHPT, hypercalcemic crisis develops during pregnancy and particularly after delivery, since calcium transport from the mother to the fetus is abruptly disrupted. Hypercalcemia may also develop in pregnant women due to PTH-related protein (PTHrP)-producing malignant tumors (humoral hypercalcemia of malignancy). Since PTHrP is produced physiologically in fetal and maternal tissues, hypercalcemia may occasionally develop during pregnancy, puerperium, and lactation due to excessive production of PTHrP in the placenta and/or mammary glands. PTHrP may also be involved in milk-alkali syndrome that develops during pregnancy. Although non-malignant hypercalcemia is usually mild, we report a 28-years-old pregnant woman who developed hypercalcemic crisis after normal delivery of an infant. On the first postpartum day, the corrected serum calcium concentration increased to 19.4 mg/dl with a markedly increased serum level of PTHrP (28.4 pmol/L) (normal <1.1 pmol/L). After administration of saline and pamidronate, the serum levels of calcium and PTHrP rapidly normalized. Extensive examination revealed no malignant lesion, suggesting that the placenta may have been producing an excessive amount of PTHrP (humoral hypercalcemia of pregnancy). We review case reports of non-malignant hypercalcemic crisis associated with pregnancy indexed in PubMed in which serum levels of intact PTH and/or PTHrP were described, and stress that rapid control of hypercalcemia is mandatory to save the life of the mother and the infant.

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Hyperinsulinemia is a known risk factor for cardiovascular events, but its molecular basis is not completely understood. In this study, we examined the effects of insulin alone, or insulin and proinflammatory cytokines, on the expression of inflammation/coagulation-related genes in hepatocytes. We found that, in the HepG2 human hepatocyte cell line, insulin stimulated the transcriptional activity of plasminogen activator inhibitor 1 (PAI-1), fibrinogen-γ and C-reactive protein (CRP) genes in time- and dose-dependent manners. These effects were completely inhibited by MAP kinase inhibitor PD98059, but not by PI3 kinase inhibitor wortmannin. As previously reported, proinflammatory cytokines like interleukin 1β and interleukin 6 showed stimulatory effects on the expression of these genes, and we now found that the combination of insulin and the cytokines showed more than additive effects in most cases. Interleukin 1β and insulin also cooperatively increased the endogenous mRNA level of PAI-1. These results suggest that the coexistence of high insulin and cytokines may induce inflammation and hypercoagulation in a synergistic manner. This may partly explain why the accumulation of multiple risk factors, especially hyperinsulinemia caused by insulin resistance and enhanced production of proinflammatory cytokines, results in inflammation, thrombosis, and cardiovascular events in metabolic syndrome.

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GH therapy was approved in 2006 for treatment of adult growth hormone deficiency (GHD) in Japan. Until then, GH was used only to treat short stature in children with GHD and the treatment was stopped when the final height was reached. In the present study, we investigated metabolic co-morbidities experienced by adults with childhood-onset (CO) GHD after the cessation of GH. Forty-two patients with COGHD (M/F 22/20, age at follow up when the retrospective analysis was carried out: 18-52 yr) treated with GH in childhood were studied. We reviewed the medical records of these patients to determine the metabolic co-morbidities that developed after cessation of GH. The median age was 19 yrs (range: 14-38) at cessation of GH, and the following co-morbidities were observed: hypertriglyceridemia in 15 (41%) patients, non-alcoholic fatty liver disease (NAFLD) in 11 (29%) patients, hypercholesterolemia in 10 (26%) patients, diabetes mellitus (DM) in 4 (10%) patients, and hypertension in 1 (2.4%) patient. The median BMI when these complications became overt was 23.5 kg/m² for those with hypertriglyceridemia, 26.0 kg/m² for those with NAFLD, 20.9 kg/m² for those with hypercholesterolemia, and 27.2 kg/m² for those with DM. More than two co-morbidities were experienced by 32% of men and 30% of women. In conclusion, adults with COGHD after the cessation of GH have multiple metabolic co-morbidities. Lifelong GH replacement might be important for improving the overall metabolic profiles in these patients.

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Anaplastic carcinoma arises from differentiated carcinoma and generally shows a dire prognosis. Anaplastic transformation may occur not only in primary tumors but also in metastatic lymph nodes. We encountered 5 cases of papillary carcinoma showing anaplastic transformation in lymph nodes that were curatively resected. Patient ages ranged from 67 to 85 years. Two of these patients showed anaplastic transformation at the initial surgery and the remaining 3 showed anaplastic transformation after repeated recurrence to the lymph nodes. After resection of anaplastic lesions of the nodes, 2 patients underwent radiation therapy, whereas the remaining 3 did not receive any adjuvant therapy. One patient died of rapid growth of lung metastasis 5 months after the resection. One patient died of carcinoma 63 months after surgery. Two patients have survived to date, 6 and 85 months after resection, respectively. The remaining one patient died of heart failure 11 months after surgery. It is therefore suggested that long-term survival can be expected for patients with differentiated carcinoma showing anaplastic transformation in the lymph node if the lesions can be curatively resected.

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Peroxisome proliferator-activated receptor-γ coactivator-1 α (PGC-1α) is a multifunctional transcriptional regulator for the pathways controlling mitochondrial biogenesis, oxidative metabolism, and glucose homeostasis. Genetic studies have suggested that Gly482Ser polymorphism of the PGC-1α gene is associated with a higher risk of type 2 diabetes, obesity, and hypertension. Adiponectin is an antidiabetic and antiatherogenic adipocytokine that is specifically produced by adipose tissue, and the transcription of the adiponectin gene is regulated by PPARγ. In this study, we examined the effect of Gly482Ser polymorphism on the plasma adiponectin level in Japanese type 2 diabetics. The Gly482Ser genotype was associated with a lower plasma adiponectin level in type 2 diabetic men, but not in type 2 diabetic women. The impact of this variation on the adiponectin promoter was also assessed by a reporter gene assay, but there was no significant difference between activation by the wild type and Gly482Ser- PGC-1α proteins, indicating that this variation itself has no functional effect. Evaluation of the pattern of linkage disequilibrium revealed that the Gly482Ser polymorphism is located in the largest linkage disequilibrium block of the PGC-1α gene. Therefore the observed gender-specific association between PGC-1α and the plasma adiponectin level may reflect linkage disequilibrium of Gly482Ser polymorphism with other causative variations.

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Aims. Heterozygous mutations of the hepatocyte nuclear factor (HNF)-4α gene cause a particular form of maturity-onset diabetes of the young (MODY1). Recent genetic studies have shown that single nucleotide polymorphisms (SNPs) of the β-cell type P2 promoter of the HNF-4α gene are associated with type 2 diabetes in some populations. In the Japanese population, a haplotype consisting of two SNPs (rs1884614 and rs2144908) in the P2 promoter region is reported to show a significant association with type 2 diabetes. Methods. Both rs1884614 and rs2144908 were genotyped in 349 type 2 diabetic patients and 203 non-diabetic controls. The relation of these SNPs to clinical characteristics was also examined in the diabetic subjects. Results. There were no differences in the genotype distribution of the two SNPs between the control and diabetic subjects, and the haplotype distribution was also similar in the two groups. However, the rs1884614 T/T genotype was significantly associated with a smaller area under the plasma insulin curve (AUC) during the OGTT in non-obese (BMI <25 kg/m ² ) patients (p = 0.0272; adjusted for age and sex). Conclusions. SNP rs1884614 in the P2 promoter region of the HNF-4α gene may influence insulin secretion in non-obese Japanese subjects with type 2 diabetes.

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The mechanism by which GnRH stimulates annexin A5 expression was examined with LβT2 gonadotrope cells. Continuous stimulation with GnRH analog (GnRHa, Des-Gly10 [Pro9]-GnRH ethylamide) transiently elevated LHβ mRNA expression while maintaining annexin A5 mRNA at high levels for 24 h. GnRH antagonist blocked the effect of GnRHa on annexin A5. While 12-O-tetradecanoyl-phorbol-13 acetate, a protein kinase C activator, increased the expression of annexin A5 mRNA, bisindolylmaleimide, an inhibitor of protein kinase C, suppressed GnRHa-stimulated expression of annexin A5 and LHβ mRNA. GnRHa stimulation of LHβ mRNA was inhibited to a greater extent than annexin A5 by a calcium chelator BAPTA/AM. Although a calcium ionophore ionomycin stimulated the expression of both genes, only LHβ was down-regulated. The MAPK kinase inhibitor PD98059 inhibited GnRHa induction of annexin A5 but not LHβ mRNA. EGF stimulated the expression of annexin A5 mRNA but caused only a transient effect on LHβ mRNA expression. These results indicate that GnRH stimulation of signaling pathway for annexin A5 mRNA expression is distinct from that of LHβ mRNA and dependent more on MAPK.

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Objectives: The optimal extent of surgery and postoperative management of patients with well differentiated thyroid carcinoma (WDTC) vary among countries and institutions. We assessed the practical management of WDTC in Korea by questionnaire and compared these results with those obtained in similar surveys of members of the Japanese Society of Thyroid Surgery (JSTS) and the International Association of Endocrine Surgeons (IAES). Materials and Methods: Questionnaires were sent by mail or e-mail to 266 members of the Korean Association of Endocrine Surgeons (KAES). Ninety members (33.8%) completed the questionnaire; their responses were compared with those of the JSTS and IAES surveys. Results: Total thyroidectomy was more prevalent in the KAES and IAES than in the JSTS, irrespective of tumor size in the low-risk group. Patients with papillary microcarcinoma were more likely to undergo aggressive central compartment node dissection in the KAES than in the IAES or JSTS. Thyroid stimulating hormone suppression therapy was administered to a higher proportion of patients and for longer times in the KAES and IAES than in the JSTS. Postoperative radioactive iodine treatment was more prevalent in the KAES than in the JSTS. There were no differences between the KAES and the JSTS in the treatment of patients with locally advanced thyroid carcinoma. External irradiation and radioactive iodine treatment for recurrent papillary thyroid carcinoma were favored more by the KAES than the IAES and JSTS. Conclusions: The actual practices of members of the KAES were almost similar to those of the IAES, but differed from those in Japan in some aspects. In general, however, members of the KAES favored more aggressive treatment of WDTC than did physicians in other countries.

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There is no recent study on the prevalence of overweight and obesity in patients with type 1 diabetes mellitus (T1DM) in Japan. Being overweight has a significant effect on the metabolic condition and glycemic control of such patients. In the present cross-sectional study, we investigated the effects of body mass index (BMI) on lipid profile, blood pressure, and glycemic control in patients with T1DM. In total, 1486 patients with T1DM (including 401 patients with early onset T1DM who were <20 years of age at diagnosis) were included. Patients were divided into four groups according to their BMI, and glycosylated hemoglobin (HbA1c), daily insulin dose per kg body weight, lipid profile, and blood pressure were compared between groups. We found that 15.7% of all patients were overweight (BMI ≥ 25.0 kg/m²) and 2.0% were obese (BMI ≥ 30.0 kg/m²), compared with 17.5% and 2.0%, respectively, in the early onset T1DM subgroup. Significant changes in lipid profiles and blood pressure were found with increasing BMI in both the entire population and the early onset T1DM subgroup. In the entire study population HbA1c and the body weight-adjusted daily insulin dose were significantly higher in patients with a BMI ≥ 23 kg/m² compared with those with a BMI<23 kg/m²; however, this was not the case in the early onset T1DM subgroup. This difference may be due to the relatively small number of patients in that subgroup. In conclusion, the prevalence of overweight and obesity in patients with T1DM was less than that in the normal Japanese population. For patients with T1DM, being overweight was associated with higher blood pressure and dyslipidemia. Furthermore, we cannot exclude an association between being overweight and the need for higher daily doses of insulin.

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ØC31 integrase can integrate targeted plasmid DNA into preferred locations in mammalian genomes, resulting in robust, long-term expression of the integrated transgene. This system represents an effective tool that opens up promising possibilities for gene therapy. The classical treatment for hypoparathyroidism was calcium and vitamin D replacement. Recently, parathyroid hormone (PTH) replacement was reported to be a more potentially physiologic treatment option. However, PTH synthesis is technically difficult and costly. These issues may be minimized by using PTH gene therapy. We attempted to achieve site-specific genomic integration of the PTH gene into a human cell line and mice using this system. We cotransfected 293 HEK cells with PTH-attB plasmid with or without ØC31 integrase plasmid. Expression and secretion of PTH into culture supernatants and site-specific genomic integration of PTH cDNA were assessed by immunoradiometric assays and pseudo-site analysis, respectively. In in vivo experiments, we injected the PTH-attB plasmid with or without ØC31 integrase plasmid into a mouse tail vein using the hydrodynamic method. Plasma PTH concentrations were serially measured, and site-specific integration of PTH cDNA into the mouse genome was confirmed by examining hepatic genomic DNA. PTH was expressed and secreted from 293 HEK cells and mouse hepatocytes, and pseudo-site analysis confirmed the site-specific integration of PTH cDNA into the host genomes. The site-specificity and efficiency of this system are advantageous in many areas, including, potentially, gene therapy. PTH gene therapy is one candidate; however, for clinical applications, we need to regulate PTH expression and secretion in the future.

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Context: The steroidogenic acute regulatory protein (StAR) is essential for the production of steroid hormones. The mutations in the StAR gene typically cause congenital lipoid adrenal hyperplasia (lipoid CAH), characterized by severe adrenal insufficiency in both sexes and complete female external genitalia in genetic males. Affected 46, XX females feminize at puberty and menstruate but have progressive hypergonadotropic hypogonadism. It has been hypothesized that the cholesterol accumulation in the steroidogenic cells destroys the residual steroidogenic capacity and progressive ovarian failure occurs (two-hit model). Additionally, ovulation and luteinization in the patients is supposed to be impaired. However, those hypotheses have not been confirmed histologically. Objective: We examined whether pathological findings of the ovary in a patient of lipoid CAH corresponded with two-hit model, and whether ovulation and luteinization occurred or not in the patient. Subject: The ovary in an adult 46, XX female with a homozygous nonsense mutation (Q258X) in the StAR gene was examined. When the patient was age 22 yr, the ovary was resected because of enlargement with polycysts and subsequent torsion. Result: The affected ovary demonstrated remarkable lipoid deposition and changes of the mitochondrial ultrastructure. Immunohistochemical examination showed decrease of steroidogenic enzymes such as P450 cholesterol side-chain cleavage (P450scc). Additionally, we detected corpus albicans in the affected ovary. Conclusion: This is the first detailed report on ovarian histology in an adult 46, XX female with a null type mutation of the StAR gene (Q258X), which indicates the evidence of the impairment of ovarian StAR-independent steroidogenesis by lipoid deposition.

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A 17-day-old Japanese boy was transferred to the hospital because of vomiting and impaired consciousness. His external genitalia was pigmented associated with small penis and penoscrotal hypospadias. He was diagnosed as suffering from adrenal deficiency according to severe electrolyte abnormality, moderate hypoglycemia, metabolic acidosis and extremely elevated 17-OHP and testosterone levels. He turned out to be a compound heterozygote of CYP21A2 mutations by genetic analysis. Through endocrinological evaluation, he seemed to have normal hypophyseal function, intact testosterone production and appropriate 5-α-reductase-2 activity. Partial androgen insensitivity could not be ruled out by slight decrease of SHBG in hCG loading test, although mutation was not detected on androgen receptor gene. This is a rare case of a male patient with 21-hydroxylase deficiency accompanied by hypospadias. As the cause of hypospadias in this case has yet to be elucidated, further investigation and careful follow-up are required.

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With recent improvements in the diagnosis and treatment of cancer, the number of childhood cancer survivors (CCSs) has been increasing in Japan. The importance of quality of life during the lifetime of CCSs has now been recognized, and the late effects of cancer treatments are essential and important issues. In this study we analyzed the endocrinological abnormalities of CCSs by retrospectively evaluating 122 outpatients (62 males and 60 females) who had been referred from pediatric oncologists to our follow-up clinic among 151 CCSs attending our hospital more than two years after their cancer treatment. Follow-up duration varied from 2 to 30 (median 8.0) years. Their average age was 17.3 (range 4-36, median 17.0) years, and 38 patients (31.1%) reached adulthood. Endocrinological abnormalities were found in 82 (67%) of 122 survivors. Gonadal dysfunction was observed in 60 patients (49%). Thirty-nine patients (32%) were short or grew at a slower rate. Twenty-six patients (21%) showed thyroid dysfunction. Other abnormalities were as follows: obesity in 20 patients (16%), leanness in 10 (8%), central diabetes insipidus in 11 (9%) and adrenocortical dysfunction in 9 (7%). Low bone mineral density was observed in 41 (42%) of 98 patients evaluated. These endocrinological abnormalities were caused by the combined effects of cancer itself and various treatments (chemotherapy, radiation therapy, surgery, and hematopoietic stem cell transplantation). Lifetime medical surveillance and continuous follow-up are necessary for CCSs, because treatment-related complications may occur during childhood and many years after the therapy as well. Endocrinologists should participate in long-term follow-up of these survivors in collaboration with pediatric oncologists.

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The purpose of this study is to evaluate the trends in age and anthropometric data for girls with Turner syndrome (TS) at start of growth hormone (GH) treatment in Japan. The data for analysis were obtained from a retrospective cohort, the Foundation for Growth Science, Japan. We analyzed trends in starting age of GH treatment for girls with TS in Japan after dividing subjects (n = 1,478) into three registration periods: 1991-1994, 1995-1999 and 2000-2004. We also assessed the ratio of the subpopulation of subjects under five years of age. As results, the mean age (standard deviation (SD)) at start of GH treatment was significantly different among the three groups (10.95 (3.63), 10.15 (3.39) and 8.78 (3.61), p<0.0001). The proportion of the subjects under five years of age increased significantly over time (5.11%, 7.11% and 16.85%, p<0.0001). Mean (SD) height SD scores were also significantly different (-3.41 (0.87), -3.26 (0.81) and -3.17 (0.79), p<0.0001). However, the proportions of the karyotype of 45,X were not significantly different among the three groups (p = 0.25). We concluded that age and shortness at initiation of GH treatment had been improving over time. However, these favorable trends have not fully met the conditions recommended by international clinical guidelines for TS.

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Brominated flame retardants (BFRs) are used to prevent combustion in consumer products. Examples of BFRs are polybrominated diphenyl ethers (PBDEs), tetrabromobisphenol A (TBBPA), and tribromophenol (TBP). These compounds are reported to have adverse effects on human health and endocrine disrupting effects. The purpose of this study was to identify the Japanese perinatal exposure to PBDEs, hydroxylated PBDE metabolites (OH-PBDEs), TBBPA, and TBP compared with polychlorinated biphenyls (PCBs) and hydroxylated PCB metabolites (OH-PCBs). We investigated the concentrations of these compounds in maternal blood, maternal milk, cord blood, and umbilical cords from 16 Japanese mother-infant pairs by HRGC/HRMS. PBDEs were detected in all samples of maternal blood (mean ± SD; median = 25 ± 23 pg/g; 18 pg/g wet weight), maternal milk (140 ± 220 pg/g; 59 pg/g wet weight), cord blood (4.8 ± 6.5 pg/g; 1.6 pg/g wet weight), and umbilical cords (3.1 ± 3.1 pg/g; 2.1 pg/g wet weight). The mothers were divided into two groups, a high-concentration group and a low-concentration group. The percentage of BDE-47 showed the greatest difference between the two groups. 6-OH-BDE-47, TBBPA, and TBP were detected in all umbilical cord samples (mean ± SD; median = 8.4 ± 8.1 pg/g; 8.0 pg/g, 16 ± 5.5 pg/g; 15 pg/g, and 33 ± 8.2 pg/g; 32 pg/g wet weight respectively), but not in all maternal blood or cord blood samples. These results indicate that OH-PBDEs, TBBPA, and TBP, in addition to PBDEs, PCBs, and OH-PCBs, pass through the blood-placenta barrier and are retained in the umbilical cord.

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Leptin has been linked to adiposity, insulin resistance, and coronary artery disease (CAD). We examined whether the leptin concentrations are associated with the risk of CAD and metabolic syndrome (MS). The plasma leptin concentrations were measured in 556 diabetic patients (341 men and 215 women). The odds ratio (OR) of CAD and MS were increased on moving from the lowest quartile (Q1) of leptin concentration to the highest quartile (Q4) and remained significant after adjusting for age, sex, BMI, concentrations of total cholesterol, triglyceride, or high-sensitivity C-reactive protein (hsCRP), and treatment modalities for hyperglycemia. The frequency of CAD was highest in the insulin resistant group (Q4 of homeostasis model assessment-insulin resistance index [HOMA-IR]) at Q4 of leptin concentration (34.5%), compared with that of Q4 of leptin (26.4%) or HOMA-IR (21.9%). In multivariate analysis, plasma leptin concentration was identified as the most significantly independent predictor for CAD (OR 10.24, 95% CI 3.01 to 45.05). Other variables with associated with CAD were age, sex, hypertension, low-HDL cholesterolemia, and hsCRP. In conclusion, hyperleptinemia might be an independent risk factor for CAD and MS in diabetic subjects. And the simultaneous measurement of insulin resistance and leptin concentration might be helpful for screening subjects with a high-risk of CAD.

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The aim of this study is to investigate the respective associations of alanine aminotransferase (ALT), white blood cell (WBC) count, and uric acid with metabolic syndrome and compare the magnitude in their association with metabolic syndrome, using modified Adult Treatment Panel III (ATP III) and its components. We studies 5,020 Korean adults (20-70 years of age; 2,501 men and 2,519 women) who visited Center for Health Promotion in Pusan National University Hospital for routine health examinations. Metabolic parameters and biochemical markers including ALT, WBC count, and uric acid were obtained. Alcohol intake, smoking status, and the presence of fatty liver were also evaluated. The prevalence of metabolic syndrome was 17.3%. In the partial correlation coefficients adjusted for age, alcohol consumption, smoking status, and presence of fatty liver, ALT was correlated significantly with all components of metabolic syndrome among three markers in men and women respectively. Moreover, ALT showed the highest correlation with HOMA-IR (r = 0.311, P<0.001 in men and r = 0.285, P<0.001 in women) in both genders. With the increase in the number of metabolic syndrome components, the mean values of all three markers were also significantly increased. In addition, the adjusted mean values of each marker were all significantly increased in metabolic syndrome. In ALT, the adjusted mean values were significantly increased in subjects with all metabolic component disorders. When we calculated odd ratios (ORs) for metabolic syndrome prevalence of the highest quartiles in three markers using multivariate logistic regression analyses, ALT was associated most strongly with metabolic syndrome in both genders (OR 5.65 [95% CI, 3.80 to 8.40]; P<0.001 in men, OR 3.23 [95% CI, 2.15 to 4.86]; P<0.001 in women). The cut-off value for ALT using the ROC curve was 27 IU/L (area under the curve = 0.717, sensitivity 62.5%, specificity 70.4%, P<0.001) in men and 18 IU/L (area under the curve = 0.735, sensitivity 61.3%, specificity 72.3%, P<0.001) in women. In conclusion, ALT, WBC count, and uric acid play important role as an additional markers for metabolic syndrome. Among three markers, in overlap the multiple risk factors, ALT might have a strong association with metabolic syndrome in Korean adults.

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The effect of ingesting seaweed "Kombu" (Laminaria japonica) on thyroid function was studied in normal Japanese adults. Ingesting 15 and 30 g of Kombu (iodine contents: 35 and 70 mg) daily for a short term (7-10 days) significantly increased serum thyrotropin (TSH) concentrations, exceeding the normal limits in some subjects. The serum free thyroxine (FT₄) and/or free 3,5,3'-triiodothyronine (FT₃) concentrations were slightly decreased within the normal limits. During long term daily ingestion of 15 g of Kombu (55-87 days), the TSH levels were elevated and sustained while the FT₄ and FT₃ levels were almost unchanged. Urinary excretion of iodine significantly increased during ingestion of Kombu. These abnormal values returned to the initial levels 7 to 40 days after discontinuing the ingestion of Kombu. Based on these findings that thyroid function was suppressed during ingestion of Kombu, though the effect was reversible, we recommend Japanese people avoid ingesting excessive amounts of seaweed.

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Black thyroid is an uncommon phenomenon of black pigmentation of thyroid parenchyma induced by chronic minocycline therapy. Thyroid tumors associated with black pigmented thyroid are rare. We describe here a 42-year-old woman with a black thyroid associated with hyalinizing trabecular tumor (HTT). The patient presented with a palpable left-sided thyroid nodule. She had taken minocycline for aphthous stomatitis and an oral ulcer for 9 years. The findings of fine needle aspiration biopsy and BRAF mutation analysis suggested a papillary carcinoma. The patient underwent a near-total thyroidectomy with central compartment node dissection. The surgical specimen showed a diffuse black thyroid and a 2-cm non-pigmented, well-circumscribed nodule in the left thyroid. Histopathologically, numerous black pigmented follicular epithelial cells and colloid were seen throughout the thyroid parenchyma, and the nodule was composed of elongated, polygonal cells in trabecular arrangement and dense hyaline stromas. The tumor cells showed a strong positive cytoplasmic reaction to Ki 67. All of these findings suggested a HTT, or a hyalinizing trabecular variant of papillary carcinoma, arising in a black thyroid. To our knowledge, this is the first case of black thyroid associated with HTT.

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We examined the endocrine profile of a boy aged 10 years and 4 months with intracranial hypotension syndrome (IHS) following a motor vehicle accident. His complaint was growth disturbance. GH secretion gradually decreased and finally was lost in spite of an epidural blood patch procedure. His height velocity was restored by GH replacement therapy. MRI and SPECT revealed damage to the hypothalamic and pituitary gland. We concluded that growth disturbance is an important sign in pediatric patients with hypothalamic damage associated with IHS.

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